title: Coordinate regulation of mature dopaminergic axon morphology by macroautophagy and the PTEN signaling pathway.
abstract: Macroautophagy is a conserved mechanism for the bulk degradation of proteins and organelles. Pathological studies have implicated defective macroautophagy in neurodegeneration, but physiological functions of macroautophagy in adult neurons remain unclear. Here we show that Atg7, an essential macroautophagy component, regulates dopaminergic axon terminal morphology. Mature Atg7-deficient midbrain dopamine (DA) neurons harbored selectively enlarged axonal terminals. This contrasted with the phenotype of DA neurons deficient in Pten - a key negative regulator of the mTOR kinase signaling pathway and neuron size - that displayed enlarged soma but unaltered axon terminals. Surprisingly, concomitant deficiency of both Atg7 and Pten led to a dramatic enhancement of axon terminal enlargement relative to Atg7 deletion alone. Similar genetic interactions between Atg7 and Pten were observed in the context of DA turnover and DA-dependent locomotor behaviors. These data suggest a model for morphological regulation of mature dopaminergic axon terminals whereby the impact of mTOR pathway is suppressed by macroautophagy.
authors.affiliation: Departments of Pathology and Neurology, Taub Institute, Columbia University Medical Center, New York, New York, United States of America.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Inoue
authors.forename: Joanne
authors.initials: J
authors.lastname: Rispoli
authors.forename: Lichuan
authors.initials: L
authors.lastname: Yang
authors.forename: David
authors.initials: D
authors.lastname: Macleod
authors.forename: M Flint
authors.initials: MF
authors.lastname: Beal
authors.forename: Eric
authors.initials: E
authors.lastname: Klann
authors.forename: Asa
authors.initials: A
authors.lastname: Abeliovich
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics; D000071193:Autophagy-Related Protein 7; D003342:Corpus Striatum / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D009024:Morphogenesis / Q000235:genetics; D009043:Motor Activity / Q000235:genetics / Q000502:physiology; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D017729:Presynaptic Terminals / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism
chemical_list: C502661:Atg7 protein, mouse; D008869:Microtubule-Associated Proteins; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D000071193:Autophagy-Related Protein 7